This research seeks to understand the metabolic basis of muscle fatigue by examining the quantitative relationship between energy metabolism and fatigability at the level of individual motor units. The specific aims are: 1) to determine the enzymatic correlates of fatigue under the appropriate stimulus conditions, 2) to determine the effect of reduced use on fatigue resistance, and 3) to determine the metabolic intermediaries associated with fatigue. The first aim should reveal the enzymes of energy metabolism which govern the ability of muscle to maintain a given force output; the second aims tests the stability of these functional correlates under conditions of induced muscle atrophy; the third measures dynamic metabolic events during fatigue which should correspond to the enzymatic phenotype. The experimental approach involves the electrophysiological characterization (i.e., axonal condition velocity, electromyography, force and fatigability) of functionally isolated motor units. The subsequent biochemical analyses of the constituent muscle fibers include: activities of enzymes (adenylokinase, creatine kinase, lactate dehydrogenase, malate dehydrogenase and beta-hydroxyacyl CoA dehydrogenase) and concentrations of phosphogens and metabolites of energy metabolism using single-fiber microflurometric assays and myosin isoform characterization using single-fiber polyacrylamide gel electrophoresis. Motor unit fibers will be identified by both glycogen depletion and 2-deoxyglucose uptake of selectively activated motor axons. Associations will be measured with statistical analyses. The proposal will provide fundamental information on the biochemical-physiological interactions that underlie muscle performance in health and in muscle disease such as Duchenne Dystrophy, Limb-Girdle Dystrophy, Motoneuron Disease, Myasthenia Gravis, Thyrotoxicosis, Progressive Muscle Atrophy, and Spinal Muscular Atrophy.